PTEN Tumor Suppressor and Signal Transduction

描述(申请人提供)：PTEN是一种肿瘤抑制因子，在大量人类癌症中被解除调控，激活致癌的磷脂酰肌醇-3激酶(PI3K)途径。PTEN的失活会导致多种表型，包括癌症、干细胞生物学的改变以及增殖和凋亡等基本过程的改变。我们最近确定，PI3K途径激活了转录抑制因子NFIL3/E4BP4。NFIL3在PTEN缺失的乳腺癌中高表达。此外，NFIL3的过度表达可见于多种预后不良的癌症。我们已经证明，NFIL3结合并招募HDAC2到启动子上，以去乙酰化组蛋白和沉默基因，甚至在多个FOXO靶基因上抑制最近发现的核FOXO蛋白池。我们的发现具有广泛的意义，表明抑制许多非FOXO靶标的NFIL3可能介导了PTEN突变导致的染色质重编程。本应用将结合生物化学、信号转导、小鼠遗传学和癌细胞生物学来解决下列目标：1)了解NFIL3改变靶基因表观遗传调控的机制；2)确定NFIL3对PTEN基因突变引起的基因表达和染色质修饰的影响；3)证明NFIL3对小鼠和细胞中PTEN突变引起的肿瘤和其他表型的贡献；以及4)确定PTEN如何调控NFIL3及其对基于PI3K的癌症治疗的意义。

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple phenotypes including cancer, changes in stem cell biology and alteration of fundamental processes such as proliferation and apoptosis. We have recently determined that the PI3K pathway activates the transcriptional repressor NFIL3/E4BP4. NFIL3 is over expressed in human breast cancers lacking PTEN. Moreover, over expression of NFIL3 is seen in multiple types of poor-prognosis cancer. We have shown that NFIL3 binds and recruits HDAC2 to promoters to deacetylate histones and silence genes and even represses a recently recognized pool of nuclear FOXO proteins at multiple FOXO target genes. Our findings have broad implications that suggest that NFIL3, which represses numerous non-FOXO targets, could mediate reprogramming of chromatin as a consequence of PTEN mutation. This application will use a combination of biochemistry, signal transduction, mouse genetics, and cancer cell biology to address the following goals 1) to understand the mechanism by which NFIL3 alters the epigenetic regulation of target genes, 2) to determine the contribution of NFIL3 to changes in gene expression and chromatin modification caused by genetic ablation of PTEN, 3) to demonstrate the contribution of NFIL3 to tumor and other phenotypes due to PTEN mutation in mice and cells, and 4) to define how NFIL3 is regulated by PTEN and its implication for PI3K- based cancer therapy.